Mitochondrial Dysfunction in Drug-Induced Liver Injury
Résumé
Mitochondrial dysfunction is a major mechanism whereby different drugs can induce liver injury such as cytolytic hepatitis, microvesicular and/or macrovacuolar steatosis, steatohepatitis, and possibly cholestasis. In the most severe cases, drug-induced mitochondrial dysfunction and liver injury can require liver transplantation or lead to the death of the patient. Moreover, these adverse effects can lead to the withdrawal of drugs from the market, or earlier during clinical trials. Drugs can induce mitochondrial dysfunction by different mechanisms including inhibition of fatty acid oxidation, impairment of oxidative phosphorylation and respiratory chain activity, and alteration of the integrity of the mitochondrial membranes. The present chapter focuses on different drugs for which enough clinical and experimental evidence indicates the potential role of mitochondrial dysfunction in the pathogenesis of liver injury acetaminophen, amiodarone, fialuridine, linezolid, nucleoside reverse transcriptase inhibitors (e.g., stavudine, zidovudine, and didanosine), tamoxifen, tetracycline, troglitazone, and valproic acid. Because drug-induced mitochondrial dysfunction and liver injury are major issues for public health and pharmaceutical companies, mitochondrial liability should be systematically investigated during preclinical safety studies. © 2018 John Wiley and Sons, Inc. All rights reserved.